1. Field of the Invention
The present invention relates to a process for preparing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by using a chiral methylhydroxylaminopropanol compound as an intermediate. More particularly, the preparation of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine includes an improved process for preparing a N-methyl-N-hydroxyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine compound.
2. Description of Related Art
(S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine®) is an antidepressant drug developed by Eli Lilly and Company, Inc. Various methods have been reported to prepare Duloxetine®. For example, U.S. Pat. No. 5,023,269 discloses a process as shown in the following scheme:

In this example, 2-acetylthiophene is used as the starting material for reacting with formaldehyde and dimethylamine to form a Mannich product, namely 3-dimethylamino-1-(2-thienyl)propan-1-one. A hydride reduction is performed on this propanone to form corresponding 3-dimethylamino-1-(2-thienyl)propan-1-ol. The resulting propanol is then reacted with fluoronaphthalene to form N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. Subsequently, racemic Duloxetine® is obtained by demethylation of this propylamine. In this process, the yield of demethylation is very low, about 41%. In addition, Duloxetine® produced via this route is racemic.
Accordingly, U.S. Pat. No. 7,538,232 discloses a process to preserve the chiral integrity by using a mixture of organic solvents. However, different types of organic solvents used in the process for the preparation of Duloxetine® increase cost for subsequent treatment. In addition, the usage of mixed organic solvents also is disadvantageous to meet the developing trends of environmental protection. Therefore, it still remains a need to provide a process for preparation of chiral Duloxetine®.